P1633: LOW SERUM BDNF LEVELS ARE ASSOCIATED WITH LOWER PLATELETS’ CD62P REACTIVITY AND INCREASED BLEEDING TENDENCY IN PATIENTS WITH GAUCHER DISEASE
Authors: D. Azoulay, M. Naamad, D. Frydman, E. Broide, A. Zimran, G. Stemer, S. Revel-Vilk
Journal: HemaSphere (2022)

Background: Recent studies suggest possible coagulative role for Brain Derived Neurotrophic Factor (BDNF), a neuronal growth factor that is stored in alpha granules of circulating platelets. Bleeding tendency, a prominent feature of patients with Gaucher disease (GD) have been shown to be associated with abnormal platelet function. Aims: We studied the serum BDNF levels in patients with GD and their correlation with platelets' function and bleeding tendency. Methods: Platelet function was analyzed in 50 patients with type I GD (F:M [%] 50:50, age [mean ± SD, range] 42.67 ± 17.92 years, 8.94 - 86.55) by an established assay designed in Shaare Zedek Medical Center, using unstimulated and stimulated [TRAP (1.5 or 20 µM), ADP (0.5 or 20 µM), ADP+Epinephrine (0.5 + 0.1 µM) and Collagen (0.25µg/mL)] flow cytometry measurement of platelet surface-activated expression of αIIbβ3 integrin (PAC1), P-selectin (CD62P), and lysosomal-associated membrane protein (LAMP3/CD63). The response to each stimulant was calculated by the delta between the unstimulated and stimulated surface-activated expression level in paired samples from the same individual patient. Total serum BDNF level was quantified using the commercial DuoSet ELISA Development System kit (R&D System DY278). Patients were divided by a high and low BDNF levels according to the normal distribution of BDNF using cutoffs points that are above the upper 25 quartiles and below the lower 25 quartiles of BDNF level. Bleeding history was conducted by bleeding tendency questioner Results: Serum BDNF levels were normally distributed in GD patients (p 0.17) and showed with similar mean and range with those of healthy controls (BDNF [mean, range] 10.72 ng/ml, 3.2-18 vs. 10.3, 1.34-25.1 in GD and healthy controls, respectively). No correlation between BDNF and Glucosylsphingosine (Lyso-Gb1) levels was detected. We found a positive correlation between BDNF levels and platelets count (r=0.39 p=0.005) and with unstimulated, Epinephrine+ADP stimulated and Collagen stimulated CD62P expression in platelets (r=0.322, p=0.02; r=0.30, p=0.03 and r=0.29, p=0.04, respectively). Patients with high serum BDNF levels (i.e. > 14 ng/ml) showed significantly higher CD62P response to TRAP, ADP+Epinephrine and Collagen as compared to patients with low serum BDNF levels (i.e.<7.8 ng/ml) (mean response in patients with high vs. low BDNF levels; 76.57 vs. 65.45, p=0.02; 33.16 vs. 18.6, p=0.04; and 80.38 vs. 70.5, p=0.03 respectively). No correlation between BDNF and expression or response in PAC1 and CD63 was observed. Patients with more than one bleeding manifestation were shown with lower BDNF levels (serum BDNF ng/ml mean ± SD in >1 vs. ≤ 1 positive bleeding history; 7.66 ± 3.21 vs. 10.98 ± 4.0 p=0.03), albeit similar platelets numbers (171 ± 97.56 vs. 183 ± 57.85, p=N.S). Summary/Conclusion: These preliminary observations demonstrate the first link between low BDNF and bleeding tendency in GD. The association between low serum BDNF levels, CD62P mediated platelets dysfunction and increased bleeding manifestation should be further studied in patients with GD as well as in other settings.